This research proposal has as its goal the development of an animal model of human alpha1-antitrypsin deficiency in order to test the hypothesis that depression of serum proteolytic inhibitory capacity (SPIC) is an important determinant in the pathogenesis of pulmonary emphysema. The depression of the SPIC will be produced by treatment of rats, hamsters, guinea pigs and mice with D-Galactosamine (D-Gal) azauridine or other agents which interfere with hepatic uridine phosphate metabolism. Drug schedules will be adjusted to produce a consistent depression of the SPIC to 50-60% of controls in one series, and to 10-20% in another. The effects of these depressions will be evaluated by their ability to increase the severity of emphysema, a)after prolonged depression of the SPIC without additional lung injury, b)after exposures to 20 ppm NO2, fly ash, combinations of NO2 and fly ash and cigarette smoke inhalation, c)by the exposure to standard doses of elastase and papain aerosol to evaluate the potentiation of the emphysema produced in the presence of depressed SPIC, and d)by evaluation of the neutralizing effect of serum protease inhibitors (PI) from animals with depressions produced by D-Gal when admixed with papain or elastase and administered by aerosol. The extent of emphysema will be evaluated objectively by measuring mean linear intercept and internal surface area. These same studies will be performed in mice with genetically determined high, low and intermediate levels of serum trypsin inhibitors. The specific protein components in serum altered by administration of D-Gal or other chemical agents, and in mice of various genetically determined levels of serum proteolytic inhibitors will be analyzed by immunoelectrophoresis, acrylamide gel electrophoresis and Sephadex column separation. The ultrastructural changes in the liver and lung produced by the D-Gal treatment and in the various genetic strains of mice will be evaluated. Special peroxidase labeled antibody studies will be performed on the inclusions within the hepatocytes to determine if they are composed of proteolytic inhibitory components, in particular alpha1-antitrypsin or its counterpart in animal serum.